Sodium hydroxide catalyzed N-alkylation of (hetero) aromatic primary amines and N1,C5-dialkylation of 4-phenyl-2-aminothiazoles with benzyl alcohols

Article abstract of DOI:10.1021/jo400834h

In the presence of a catalytic amount of NaOH, the selective N-alkylation of various heteroaromatic primary amines is reported. With 1 equiv of NaOH, N₁,C₅-dialkylation of 4-phenyl-2-aminothiazoles has been investigated. Reaction of in situ generated aldehyde with amine yields the N-alkylated and N₁,C₅-dialkylated products through hydride ion transformation from alcohol.

Full text of DOI:10.1021/jo400834h

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Note
Sodium Hydroxide Catalysed N–Alkylation of
(Hetero)Aromatic Primary Amines and N1, C5- Dialkylation
of 4-Phenyl -2- aminothiazoles with Benzyl Alcohols
Ramachandra Reddy Donthiri, Venkatanarayana Pappula, Darapaneni
Chandra Mohan, Hiren H Gaywala, and Subbarayappa Adimurthy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400834h • Publication Date (Web): 14 Jun 2013
Downloaded from http://pubs.acs.org on June 14, 2013
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Sodium Hydroxide Catalysed N-Alkylation of (Hetero) Aromatic Primary
Amines and N1, C5 - Dialkylation of 4-phenyl -2-aminothiazoles with Benzyl
Alcohols
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Ramachandra Reddy Donthiri,a Venkatanarayana Pappula,a Darapaneni Chandra Mohan,a
Hiren H. Gaywalab and Subbarayappa Adimurthy* a
aAcademy of Scientific & Innovative Research, CSIR–Central Salt & Marine Chemicals
Research Institute, G.B. Marg, Bhavnagar-364 002. Gujarat (INDIA); adimurthy@csmcri.org
bDissertation student at CSIR-CSMCRI.
Abstract.
In the presence of catalytic amount of NaOH, the selective N-alkylation of various
heteroaromatic primary amines is reported. With one equivalent of NaOH, N1, C5-
dialkylation of 4-phenyl-2-aminothiazoles has been investigated. Reaction of in-situ
generated aldehyde with amine yields the N-alkylated and N1, C5-dialkylated products
through hydride ion transformation from alcohol.
The C–N bond forming reactions has attracted enormously over the last two decades
and find its application in all areas of organic chemistry, ranging from the laboratory bench,
to the synthesis of pharmaceutical fine chemicals and the production of bulk chemicals.1-4
Among the C–N bond forming reactions the N-alkylation of primary amines is an important
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due to tremendous utility of these amines in industries for the synthesis of dyes, additives,
agrochemicals, functional materials and pharmacophores for the synthesis of bioactive
molecules.5-8 Arguably, the direct N-alkylation of amines with alcohols is most desirable, due
to the ready and inexpensive availability of wide range of alcohols and theoretically produces
only water as a by-product. In this regard many groups have achieved N-alkylation of amines
with alcohols using transition metal/metal complexes as catalysts through borrowing
hydrogen methodology.9 Beside all these recent advancements, major drawbacks of these
methods are requirement of transition metal catalysts to promote this transformation
efficiently. Thus, transition metal separation from organic products is of particular
importance for the synthesis of pharmaceutical fine chemicals because of their residual
toxicity in the target compounds is a central issue to consider, hence the development of more
improved synthetic routes without transition metal is desirable. Although transition metal-
free N-alkylation of amines with alcohols were known but reactions demand harsh conditions
such as high temperature (250-300 °C), high pressure, very long reaction time (10 days),
strong basic conditions, and large excess of alcohols or amines, consequently low yields and
poor selectivities were reported.10-16 Very recently Qing Xu and co-workers reported the
transition metal-free N-alkylation of sulphonamides and aromatic amines in presence of base
(10-100 mol%) and external addition of catalytic amount of aldehyde.17
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Recently, we have reported the transition metal-free imine synthesis through activation
of alcohol by base in presence of amines.18,19 In continuation of our efforts to explore C–N
bond forming reactions,20-24 we sought to investigate the direct N-alkylation of hetero
aromatic primary amines with alcohols using NaOH as catalyst (20 mol%) under transition
metal-free conditions.
2-Aminobenzothiazoles and thiazoles are versatile synthetic intermediates and are
widely used in the synthesis of various biologically active compounds.25-30 Particularly, N-
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alkylated thiazoles and benzothiazoles exhibit different pharmacological and physiological
activities.31,32 As a result, much attention has been paid for the synthesis of these
compounds.33-39 By considering the importance of 2-aminobenzothiazole derivatives, we
investigated herewith the N-alkylation of 2-amino benzothiazoles and the method has been
extended to other heteroaromatic amines including pyridine, pyrimidine and pyrazines with
various alcohols. Under these conditions we found the N1, C5-dialkylation of 4-phenyl-2-
aminothiazoles and there were no reports found for this type of transformation.
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At the start of our studies, we investigated the N-alkylation of 2-aminobenzothiazole 1a
with 4-chloro benzyl alcohol 2a as alkylating agent and results are illustrated in Table 1. In
the presence of NaOH in toluene at room temperature no product 3a was formed (Table 1,
o
entry 1). When the reaction is performed at 100 C, the N-alkylated product was observed
with 80% GC-yield (Table 1, entry 2). Conversion reached to 100% (93% isolated), when the
reaction temperature was increased to 120 oC (Table 1, entry 3). However, the reaction does
not proceed efficiently in other solvent system (Table 1, entries 4-8). Alternately, screening
of different bases (KOH, Na2CO3, K2CO3, KOtBu, and NaOtBu) was performed (Table 1,
entries 9-13). After extensive screening of various bases and solvents, NaOH showed good
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activity and selectivity in toluene at 120 C and the similar yield (93%) was observed even
with 20 mol% of NaOH (Table 1, entry 14), reaction completely retarded in absence of
NaOH (table 1 entry 15). To rule out the catalytic activity of trace impurities of transition
metals in commercially available NaOH, two experiments were performed using pure Na
metal and NaH (Table 1, entries 16 and 17). These species also provided similar yield and
selectivity of the product for the present transformation. These facts supports that, the role of
catalytic activity of trace metal impurities from the commercial NaOH is less probable. To
examine the role of oxygen, the reaction was performed under nitrogen atmosphere, it was
also provided 90% isolated yield of 3a (Table 1, entry 18). Further, 2a was subjected to
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oxidation in absence of amine under open and nitrogen atmosphere, only 2% and 1% yield of
aldehyde was observed respectively (Table 1, entries 19 and 20). Oxidation under nitrogen
atmosphere may be due to the presence of trace amount of oxygen from the commercial
cylinder. These reactions clearly indicate that, the in-situ generated catalytic aldehyde is
responsible for the current transformation.
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Table 1. Optimization of reaction conditions for 3aa
entry base
solvent
yield (%)b
1c
2d
3
4
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8
NaOH
toluene
toluene
toluene
DMF
DMSO
H2O
---
80
100(93)
---
---
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
---
---
glycerol
chloro benzene 70
9
KOH
toluene
toluene
toluene
85
---
30
87
95
100(93)
---
100
100
100(90)
2
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14e
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18f
19e,g
Na2CO3
K2CO3
NaOtBu toluene
KOtBu
NaOH
---
toluene
toluene
toluene
Na metal toluene
NaH
NaOH
NaOH
toluene
toluene
toluene
toluene
20e,f,g NaOH
1
aReaction conditions unless otherwise stated: 1a (1.0 mmol), 2a
o
(1.2 mmol), base (1.0 mmol), solvent (1.0 mL), 120 C, 15 h,
under atmospheric air. GC yields. Room temperature. 100 °C.
eNaOH 20 mol %. Nitrogen atmosphere. Without 1a yield refers
to corresponding aldehyde (See figs. S2-S6 in supporting
information for entries 19 and 20). Numbers in parenthesis are
isolated yield.
b
c
d
f
g
The scope of the reaction was then investigated with 2-aminobenzothiazoles and benzyl
alcohols as alkylating agents (Table 2). Under these optimized conditions, various substituted
benzyl alcohols reacted with 2-aminobenzothiazole to yield the corresponding N-alkylated
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products in good yield. Benzyl alcohols having electron donating (methyl or methoxy) groups
transformed into N-alkylated 2-aminobenzothiazoles in high yield (3b-d). Electronic effects
associated with electron- withdrawing substituents (Cl, Br) on the phenyl ring (either o/m/p)
does not affect the efficiency of the N-alkylation of 2-aminobenzothiazole (3e-g).
Table 2. N-Alkylation of various hetero amines with benzyl alcoholsa
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aReaction conditions unless otherwise stated: amine (1 mmol), alcohol (1.2
mmol), NaOH (20 mol %), toluene (1 mL), 120° C, 15 h; isolated yield.
Unsubstituted benzylic alcohol and hetero benzylic alcohol (pyridin-3-ylmethanol) too
provided the desired products in excellent yield (3h, 3i). The N-alkylation of different
substituted 2-aminobenzothiazoles was then studied. N-Alkylation of 2-aminobenzothiazoles
bearing electron releasing (Me) and electron withdrawing (halogen) groups afforded the
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corresponding N-alkylated products in 82-91% yield (3j-p). Remarkably 4, 5-diphenyl 2-
aminothiazole was also given required products in good yields (3q, 3r). Notably the products
(3a-r) were purified without column chromatography (See the typical procedure). Further we
have extended the present transformation to other hetero aromatic amines such as 2-amino
pyrimidine, 2-amino pyridine and amino pyrazine. These heterocyclic amines also afford
good to excellent yields of N-alkylated products (3s-3z) irrespective of alcohols under the
optimised conditions. No desired products were observed with other alcohols such as
cyclohexanol, n-heptanol, 3-methylbut-2-en-1-ol and cinnamyl alcohol.
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Having developed a synthetic method for N-alkylation of heteroamines, we finally
explored the current concise transformation for dialkylation of 4a (Scheme 1). The optimized
conditions of table 2, were applied to 4a, with benzyl alcohol as alkylating agent, a mixture
Scheme 1.
of di- and mono-alkylated products 5a and 5a' were obtained. Under these conditions, the
formation of dialkylated product 5a was quite interesting, and no such reports exist in
literature. Hence we became interested to investigate the conditions for selective formation of
a single dialkylated product 5a. The identified conditions for this transformation were three
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equivalents of benzyl alcohol, one equivalent amine 4a at 130 C in toluene and 28 h of
reaction time. These revised optimum conditions were applied to explore the synthesis of N1,
C5-dialkyl-4-phenylthiazol-2-amines (Table 3). It was found that N1, C5-dialkylation of 4a
proceeded smoothly with benzylic alcohols having electron-releasing and withdrawing
substituents (2a-c) to give corresponding products (5a-c) in good yields. Similarly, the
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presence of electron-releasing/withdrawing groups on 4-phenylthiazol-2-amines afforded the
corresponding dialkylated products (5d-l) in good yields with irrespective of benzlylic
alcohols. Under these conditions dialkylation of unsubstituted 2-aminothiazole was not
observed as it undergoes charring. The formation of 5h was further confirmed by single-
crystal XRD (See Fig S1).
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Table 3. N1, C5-Dialkylation of 4-phenyl 2-aminothiazoles with various alcoholsa
aReaction conditions unless otherwise stated: amine 4 (1 mmol), alcohol
2 (3 mmol), NaOH (1.0 mmol), toluene (1 mL), 130 °C, 28 h; Isolated
yield. bReaction time 36 h.
The formation of di alkylated product may be due to the electron rich nature of five
membered thiazole compared to six membered pyridine, pyrimidine and pyrazine systems.
The substitution of phenyl ring at C4 may further increase the electron density on C5 of 4a.
Further to confirm the current transformation we performed reaction starting from imine
(Scheme 2), under the same reaction conditions, 70% of dialkylated product 5c was isolated
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Scheme 2. Mechanistic experiment
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along with 68% of 4-chloro benzoic acid after work-up. Based on the above experimental
evidence and previous reports,17–19 we proposed a plausible mechanism (Scheme 3). Initially,
alcohol was partly oxidised to aldehyde in presence of NaOH and air as an oxidant.40,41 The
reaction of aldehyde and amine 4a generate imine intermediate A. In presence of base,
dehydrogenation of alcohol with simultaneous hydrogenation of imine lead to aldehyde and
N-alkylated product B respectively. Nucleophilic addition of B to aldehyde may form
iminoalcohol C, and its dehydration gives another intermediate D. Through hydride ion
transfer process, it provides the final product E.
Scheme 3. Possible mechanism for the N1, C5-dialkylation of 4-phenyl 2-aminothiazole.
In summary, we have developed a novel method for N-alkylation of hetero amines with
benzylic alcohols as alkylating agents in presence of catalytic NaOH under mild conditions.
Reaction of 4-phenylthiazol-2-amines with benzyl alcohols gave N1, C5-dibenzyl-4-
phenylthiazol-2-amines in good yields with one equivalent of NaOH. Compared to previously
known transition metal catalysts, NaOH is inexpensive, readily available, convenient to use
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without any special precautions. The method is applicable for a wide range of benzylic
alcohols as alkylating agents.
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EXPERIMENTAL SECTION
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General: All commercially available chemicals and reagents were used without any further
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purification unless otherwise indicated. H and C NMR spectra were recorded at 500/200,
and 125/50 MHz, respectively. The spectra were recorded in DMSO as solvent. Multiplicity
was indicated as follows: s (singlet); d (doublet); t (triplet); m (multiplet); dd (doublet of
doublets), etc. Coupling constants (J) were given in Hz. Chemical shifts are reported in δ
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relative to TMS as an internal standard. The peaks around δ values of H NMR (2.5), C
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NMR (39.4) are correspond to deuterated DMSO and δ value (3.3) in H NMR is of water.
Progress of the reactions was monitored by thin layer chromatography (TLC). Silica gel 100-
200 mesh size was used for column chromatography.
Typical procedure for synthesis of (3a): In a 25 mL round bottomed flask, 150 mg (1.0
mmol) of 2-amino benzothiazole (1a), 171 mg (1.2 mmol) of 4-chloro benzyl alcohol (2a), 8
mg (0.2 mmol) of sodium hydroxide (NaOH) and 1.0 mL of toluene were placed. The
reaction flask was heated at 120 °C for 15 h in an oil bath. After completion of the reaction,
the flask allowed to attaining room temperature, and toluene was removed under reduced
pressure. To the residue 20 mL of water was added, stirred for 5 min on magnetic stirrer at
room temperature and the solid was collected through filtration and washed with 10% ethyl
acetate in hexane (10 mL) solution to get white solid in 93% yield (255 mg; 0.93 mmol) of
3a. [Note: The products (3a-r) obtained were pure (by NMR analysis) without separation by
column chromatography, but by simple solvent wash. The products obtained from liquid and
solid benzylic alcohols were washed with only hexane and ethylacetate/hexane (1:9)
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respectively. Products 3s–z were purified by column chromatography (the eluent for products
3s-3w (9:1) and for the products 3x-3z (7:3) ethylacetate/hexane).
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Charecteristion data of all compounds:
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N-(4-chlorobenzyl)benzo[d]thiazol-2-amine (3a)33:
1
Yield 93% (255 mg); H NMR (500 MHz, DMSO): δ 4.58(d, J = 6 Hz, 2H), 7.03(t, J = 7.5
Hz, 1H),7.22 (t, J = 7.5 Hz, 1H), 7.38 – 7.40 (m, 5H), 7.66 (d, J = 7.5 Hz , 1H) 8.54 (t, J = 6
Hz, 1H); 13C NMR (125 MHz, DMSO): 46.8, 118.5,121.3, 121.5, 126.0, 128.7, 129.6, 130.8,
131.9, 138.4, 152.7, 166.5.
N-(4-methylbenzyl)benzo[d]thiazol-2-amine (3b)33 :
1
Yield 94% (239 mg); H NMR (500 MHz, DMSO): δ 2.27 (s, 3H), 4.54 (d, J = 5 Hz, 2H),
7.02 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 8, 2H), 7.22 (t, J = 8 Hz, 1H), 7.26 (d, J = 8 Hz, 2H),
7.38 (d, J = 8, 1H), 7.65 (d, J = 8 Hz, 1H), 8.47 (t, J = 5, 1H) ; 13C NMR (125 MHz, DMSO):
23.0, 49.3, 120.4, 123.2, 127.8, 129.7, 131.2, 132.7, 138.1, 138.4, 154.8, 168.5.
N-(4-methoxybenzyl)benzo[d]thiazol-2-amine (3c)33 :
1
Yield 96% (259 mg); H NMR (500 MHz, DMSO): δ 3.72 (s, 3H), 4.51 (d, J = 5 Hz, 2H),
6.89 (d, J = 7 Hz, 2H), 7.01 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 7.5 Hz,
2H), 7.38 (d, J = 8 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 8.42(s, 1H) ; 13C NMR (125 MHz,
DMSO): 49.0, 57.3, 116.1, 120.3, 123.2, 127.8, 131.1, 132.7, 133.1, 154.8, 160.7, 168.4.
N-(3-methoxybenzyl)benzo[d]thiazol-2-amine (3d):
Yield 91% (246 mg); 1H NMR (500 MHz, DMSO): δ 3.73 (s, 3H), 4.56 (d, J = 5.5 Hz, 2H),
6.82 (d, J = 8 Hz, 1H), 6.94 (d, J = 6.5 Hz, 2H), 7.02 (t, J = 7.5 1H), 7.20 – 7.27 (m, 2H),
13
7.38 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 8.49 (t, J = 5.5 Hz, 1H); C NMR (125
MHz, DMSO): 47.1, 54.9, 112.2, 112.9, 118.0, 119.4, 120.8, 125.4, 129.3, 130.3, 140.4,
152.34, 159.2, 166.1; IR(KBr): 672, 751, 796, 978, 1043, 1163, 1264, 1342, 1451, 1566,
1612, 2896, 3464; HRMS calcd for C15H15N2OS: 271.0906, found: 271.0934.
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N-(2-chlorobenzyl)benzo[d]thiazol-2-amine (3e)33 :
5
6
1
Yield 80% (219 mg); H NMR (500 MHz, DMSO): δ 4.67 (d, J = 5.5 Hz, 2H), 7.03 (t, J =
7
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7.5 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.30 – 7.35 (m, 2H), 7.38 (d, J = 8.0 Hz , 1H), 7.47 (s,
2H), 7.67 (d, J = 7.5 Hz, 1H), 8.53 (s, 1H) ; 13C NMR (125 MHz, DMSO): 47.3, 120.5,
123.3, 123.4, 127.8, 129.5, 131.2, 131.4, 131.5, 132.8, 134.6, 138.2, 154.6, 168.3.
N-(3-chlorobenzyl)benzo[d]thiazol-2-amine (3f):
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Yield 94% (257 mg); 1H NMR (500 MHz, DMSO): δ 4.60 (d, J = 6 Hz, 2H), 7.04 (t, J = 7.5
Hz, 1H), 7.23 (t, J = 7 Hz, 1H),7.33 (t, J = 8.5 Hz, 2H), 7.37 – 7.40 (m, 2H), 7.42 (s, 1H),
13
7.67 (d, J = 8.0 Hz, 1H); 8.56 (t, J = 6Hz, 1H); C NMR (125 MHz, DMSO): 46.9, 118.6,
121.4, 126.0, 126.4, 127.4, 127.5, 130.7, 130.8, 133.5, 142.1, 152.7, 166.6; IR(KBr): 677,
755, 865, 975, 1075, 1116, 1221, 1261, 1339, 1446, 1566, 1609, 2899, 2981, 3086, 3137,
3179, 3473. HRMS calcd for C14H12ClN2S: 275.041, found: 275.0412.
N-(4-bromobenzyl)benzo[d]thiazol-2-amine (3g)33 :
1
Yield 94% (300 mg); H NMR (500 MHz, DMSO): δ 4.56 (d, J = 5.5 Hz, 2H), 7.02 (t, J =
7.5 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 8Hz, 2H), 7.37 (d, J = 8Hz , 1H), 7.53 (d, J
= 8 Hz, 2H), 7.66 (d, J = 7.5 Hz, 1H), 8.53 (t, J = 5 Hz, 1H); 13C NMR (125 MHz, DMSO);
48.7, 120.5, 122.3, 123.3, 123.3, 127.8, 131.8, 132.7, 133.5, 140.8, 154.6, 168.4.
N-benzylbenzo[d]thiazol-2-amine (3h)33:
1
Yield 96% (230 mg); H NMR (500 MHz, DMSO): δ 4.60 (d, J = 5.5 Hz, 2H), 7.02 (t, J =
7.5 Hz, 1H), 7.20 – 7.27 (m, 2H), 7.33 – 7.40 (m, 5H), 7.66 (d, J = 8Hz, 1H), 8.52 (t, J = 5
Hz, 1H) ;13C NMR (125 MHz, DMSO): 47.4, 118.4, 121.3, 125.8, 127.3, 127.6, 128.6, 130.6,
139.2, 152.7, 166.5.
N-(pyridin-3-ylmethyl)benzo[d]thiazol-2-amine (3i):
Yield 93% (224 mg); 1H NMR (500 MHz, DMSO): δ 4.62 (d, J = 5.5 Hz , 2H), 7.03 (t, J =
7.5 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.36-7.41 (m, 2H), 7.67 (d, J = 7.5 Hz, 1H), 7.78 (d, J =
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8 Hz, 1H), 8.47 (d, J = 4 Hz, 1H), 8.56 (t, J = 5.5 Hz, 1H), 8.61 (s, 1H); C NMR (125
MHz, DMSO): 45.2, 118.7, 121.4, 121.6, 123.9, 126.0, 130.9, 134.9, 135.7, 148.7, 149.3,
152.7, 166.5; IR (KBr): 629, 705, 762, 1049, 1101, 1122, 1208, 1433, 1538, 2362, 2921,
3167, 3428. HRMS calcd for C13H12N3S: 242.0753, found: 242.0774.
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4-methyl-N-(4-methoxybenzyl)benzo[d]thiazol-2-amine (3j):
Yield 91% (258 mg); 1H NMR (500 MHz, DMSO): δ 2.44 (s, 3H), 3.72 (s, 3H), 4.48 (d, J = 6
Hz, 2H), 6.89 – 6.92 (m, 3H), 7.03 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.46(d, J = 8
Hz, 1H), 8.41(t, J = 5.5 Hz, 1H); 13C NMR (125 MHz, DMSO): 18.8, 47.6, 55.7, 114.4,
119.0, 121.4, 126.9, 127.9, 129.7, 130.5, 131.5, 152.0, 159.1, 166.1; IR (KBr): 625, 702, 755,
810, 833, 869, 888, 925, 963, 1027, 1069, 1174, 1215, 1245, 1285, 1353, 1404, 1449, 1513,
1534, 1594, 1762, 1828, 2362, 2626, 2839, 2914, 3231, 3866. HRMS calcd for C16H17N2OS:
285.1062 found: 285.1031.
N-benzyl-4-methylbenzo[d]thiazol-2-amine (3k):
1
Yield 87% (221 mg); H NMR (500 MHz, DMSO): δ 2.43 (s, 3H), 4.57 (d, J = 5.5 Hz, 2H),
6.91 (t, J = 8 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 7.26 (t, J = 7 Hz, 1H), 7.34 (t, J = 8 Hz, 2H),
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7.40 (d, J = 7 Hz, 2H), 7.46 (d, J = 7.5 Hz, 1H), 8.48 (t, J = 5.5 Hz, 1H); C NMR (125
MHz, DMSO): 18.0, 47.3, 118.2, 120.7, 126.1, 126.9, 127.1, 127.5, 128.2, 129.7, 138.8,
151.2, 165.4; IR (KBr): 617, 689, 742, 771, 881, 1027, 1077, 1209, 1242, 1453, 1523, 1556,
1644, 1733, 2359, 2921, 3209, 3437, 3645, 3732, 3796, 3922. HRMS calcd for C15H15N2S:
255.0956, found: 255.0948.
N-benzyl-6-methylbenzo[d]thiazol-2-amine (3l)33:
Yield 90% (228 mg); 1H NMR (500 MHz, DMSO): δ 2.30 (s, 3H), 4.58 (d, J = 5.5 Hz, 2H),
7.01 (d, J = 8 Hz, 1H), 7.24 – 7.28 (m, 1H), 7.32 – 7.38 (m, 4H), 7.45 (s, 1H), 8.39 (t, J =
5.5Hz, 1H) ;13C NMR (125 MHz, DMSO): 21.2, 47.6, 118.2, 121.3, 127.0, 127.4, 127.8,
128.8, 130.5, 130.9, 139.4, 150.7, 166.0.
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N-(4-chlorobenzyl)-6-methylbenzo[d]thiazol-2-amine (3m):
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Yield 83% (239 mg); H NMR (500 MHz, DMSO): δ 2.31 (s, 3H), 4.56 (d, J = 5 Hz, 2H),
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7.02 (d, J = 8 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.39 (s, 4H), 7.46 (s, 1H), 8.42 (t, J = 5 Hz,
1H) ;13C NMR (125 MHz, DMSO): 21.2, 46.8, 118.3, 121.3, 127.0, 128.7, 129.6, 130.6,
130.9, 132.0, 138.6, 150.6, 165.9 ; IR (KBr): 677, 729, 814, 1014, 1086, 1262, 1348, 1464,
1616, 2364, 2854, 2912, 3452; MS m/z 289 [M + H]+, 243, 242, 214, 186, 125, 128, 104.
CHNS calcd for C15H13ClN2S: C (62.38), H (4.54), N(9.70), S (11.1), found: C (62.41), H
(4.52), N (9.72), S (11.07).
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6-Chloro-N-(4-chlorobenzyl)benzo[d]thiazol-2-amine (3n):
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Yield 90% (278 mg); H NMR (500 MHz, DMSO): δ 4.58 (d, J = 6Hz, 2H), 7.23 (dd, J1 =
6.5Hz, J2 = 2Hz, 1H), 7.35 – 7.42 (m, 5H), 7.80 (d, J = 2Hz, 1H), 8.67 (t, J = 6Hz, 1H); 13C
NMR (125 MHz, DMSO): 46.9, 119.4, 121.1, 125.2, 126.1, 128.8, 129.6, 132.1, 132.5,
138.2, 151.7, 167.2; IR (KBr): 682, 726, 767, 815, 1090, 1257, 1345, 1445, 1570, 1613,
2360, 2903, 3085, 3452. HRMS calcd for C14H11Cl2N2S: 309.0021, found: 309.0016.
6-Chloro-N-(4-methoxybenzyl)benzo[d]thiazol-1-amine (3o):
1
Yield 82% (249 mg); H NMR (200 MHz, DMSO): δ 3.72 (s, 3H), 4.49 (d, J = 4.6 Hz, 2H),
6.88 (d, J = 8.2 Hz, 2H), 7.19 – 7.38 (m, 4H), 7.77 (s, 1H), 8.55 (s, 1H); 13C NMR (50 MHz,
DMSO): 47.2, 55.4, 114.2, 119.3, 121.0, 125.1, 126.1, 129.3, 130.9, 132.5, 151.8, 158.9,
167.2; IR (KBr): 607, 767, 821, 1031, 1172, 1250, 1345, 1446, 1509, 1547, 1567, 1603,
2842, 2971, 3174, 3411. HRMS calcd for C15H14ClN2OS: 305.0516, found: 305.0517.
N-benzyl-6-chlorobenzo[d]thiazol-2-amine (3p)33:
Yield 89% (244 mg); 1H NMR (500 MHz, DMSO): δ 4.59 (d, J = 6 Hz, 2H), 7.22 – 7.28 (m,
13
2H), 7.33 – 7.38 (m, 5H), 7.79 (d, J = 2.5 Hz, 1H), 8.62 (t, J = 6Hz, 1H); C NMR (125
MHz, DMSO): 47.7, 119.4, 121.1, 125.1, 126.1, 127.5, 127.8, 128.8, 132.5, 139.1, 151.8,
167.3.
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N-benzyl-4,5-diphenylthiazol-2-amine (3q):
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Yield 85% (290 mg); 1H NMR (500 MHz, DMSO): δ 4.49 (d, J = 5.5 Hz, 2H), 7.19 (d, J = 7
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Hz, 2H), 7.23 – 7.30 (m, 7H), 7.34 – 7.41 (m, 6H), 8.26 (t, J = 6 Hz, 1H); C NMR (125
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MHz, DMSO): 47.4, 118.7, 126.9, 127.0 127.2, 127.4, 127.9, 128.2, 128.4, 128.6, 128.8,
132.5, 135.3, 139.0, 144.8, 165.8. IR (KBr): 690, 760, 971, 1068, 1230, 1324, 1417, 1580,
1956, 2356, 2962, 3085, 3195, 3416; HRMS calcd for C22H19N2S: 343.1269, found:
343.1266.
N-(4-chlorobenzyl)-4,5-diphenylthiazol-2-amine (3r):
1
Yield 80% (300 mg); H NMR (500 MHz, DMSO): δ 4.48 (d, J = 6 Hz, 2H), 7.19 (d, J = 7
Hz, 2H) , 7.24 – 7.30 (m, 6H), 7.38 (d, J = 6.5 Hz, 2H), 7.4 (s, 4H), 8.28 (t, J = 6Hz, 1H);
13C NMR (125 MHz, DMSO): 47.3, 119.7, 127.8, 128.0, 128.7, 128.9, 129.1, 129.4, 129.6,
130.0, 132.2, 133.2, 136.0, 138.9, 145.6, 166.4. IR (KBr): 694, 759, 1082, 1218, 1318, 1420,
1485, 1563, 1770, 1894, 1960, 2349, 2893, 2959, 3075, 3197, 3418; MS m/z 399 [M + Na]+,
377 [M + H]+, 375, 331, 302, 301, 261, 223, 217, 156, 140, 97, 81; CHNS calcd for
C22H17ClN2S: C (70.11), H (4.55), N (7.43), S (8.51), found: C (70.17), H (4.55), N(7.40), S
(8.48).
N-benzylpyrimidin-2-amine (3s)17:
Yield 91% (168 mg); 1H NMR (500 MHz, DMSO): δ 4.49 (d, J = 6 Hz, 2H), 6.56(t, J = 5 Hz,
1H) 7.18 – 7.21 (m, 1H), 7.27 – 7.29 (m, 4H), 7.70 (t, J = 5 Hz, 1H), 8.25 (d, J = 5Hz, 2H);
13C NMR (125 MHz, DMSO): 44.5, 110.8, 127.1, 127.6, 128.7, 141.07, 158.6, 162.9.
N-(4-methylbenzyl)pyrimidin-2-amine (3t)17:
Yield 90% (179 mg); 1H NMR (500 MHz, DMSO): δ 2.25(s, 3H), 4.43 (d, J = 6.5 Hz, 2H),
6.55(t, J = 4.5 Hz, 1H) 7.08(d, J = 7.5 Hz, 2H), 7.17(d, J = 8 Hz, 2H), 7.62 (t, J = 6.5 Hz,
13
1H), 8.24 (d, J = 5Hz, 2H); C NMR (125 MHz, DMSO): 21.3, 44.2, 110.8, 127.6, 129.3,
136.1, 138.0, 158.6, 162.9.
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N-(4-chlorobenzyl)pyrimidin-2-amine (3u)17:
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Yield 93% (204 mg); 1H NMR (500 MHz, DMSO): δ 4.45 (d, J = 6.5 Hz, 2H), 6.57(t, J = 5
Hz, 1H) 7.30 – 7.35 (m, 4H), 7.72 (t, J = 6.5 Hz, 1H), 8.25 (d, J = 5Hz, 2H); 13C NMR (125
MHz, DMSO): 43.9, 111.0, 128.7, 129.5,131.6, 140.2, 158.6, 162.8.
N-benzylpyridin-2-amine (3v)17:
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Yield 90% (165 mg); H NMR (500 MHz, DMSO): δ 4.46 (d, J = 6 Hz, 2H), 6.46 (t, J = 6
Hz, 1H), 6.49 (d, J = 8.5 Hz, 1H) 7.01 (t, J = 5.5 Hz, 1H), 7.20 (t, J = 7 Hz, 1H), 7.27 – 7.36
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(m, 5H), 7.94 (d, J = 5 Hz, 1H); C NMR (125 MHz, DMSO): 44.8, 108.8, 112.3, 127.1,
127.8, 128.8, 137.3, 141.3, 148.2, 159.3.
N-(4-methylbenzyl)pyridin-2-amine (3w)17:
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Yield 92% (182 mg); H NMR (500 MHz, DMSO): δ 2.25 (s, 3H), 4.40 (d, J = 6 Hz, 2H),
6.44 – 6.48 (m, 2H), 6.94 (s, 1H), 7.09 (d, J = 7 Hz, 2H), 7.19 (d, J = 7.5 Hz, 2H), 7.33 (t, J
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= 7.5 Hz, 1H), 7.93 (d, J = 3.5 Hz, 1H); C NMR (125 MHz, DMSO): 21.3, 44.5, 108.7,
112.3, 127.8, 129.4, 136.1, 137.2, 138.2, 148.2, 159.3.
N-benzylpyrazin-2-amine (3x):
Yield 92% (170 mg); 1H NMR (500 MHz, DMSO): δ 4.47 (d, J = 6 Hz, 2H), 7.21 – 7.25 (m,
1H), 7.30 – 7.34 (m, 4H), 7.58 (t, J = 5.5 Hz, 1H), 7.65(d, J = 3 Hz, 1H), 7.91 (s, 1H),
7.97(s, 1H); 13C NMR (125 MHz, DMSO): 44.2, 127.4, 127.9, 128.9, 131.9, 133.9, 140.4,
142.2, 155.5; IR (KBr): 696, 753, 822, 1001, 1056, 1324, 1426, 1567, 1771, 1897, 2356,
3039, 3088, 3231, 3425; HRMS calcd for C11H12N3: 186.1031, found: 186.1010.
N-(4-methylbenzyl)pyrazin-2-amine (3y):
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Yield 90% (179 mg); H NMR (500 MHz, DMSO): δ 2.26 ( s, 3H), 4.41 (d, J = 6 Hz, 2H),
7.11(d, J = 7.5, Hz, 2H), 7.20 (d, J = 8 Hz, 2H), 7.51 (d, J = 5 Hz, 1H), 7.64 (d, J = 2.5 Hz,
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1H), 7.90 (s, 1H), 7.95 (s, 1H); C NMR (125 MHz, DMSO): 21.3, 44.0, 127.9, 129.5,
131.85, 133.9, 136.4, 137.3, 142.1, 155.5; IR (KBr): 686, 807, 1002, 1050, 1103, 1144,
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1198, 1329, 1429, 1571, 1910, 2358, 2996, 3094, 3231, 3427; HRMS calcd for C12H14N3:
200.1188, found: 200.1176.
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Yield 91% (199 mg); 1H NMR (500 MHz, DMSO): δ 4.46 (d, J = 6 Hz, 2H), 7.33 – 7.38 (m,
4H), 7.62 (t, J = 6Hz, 1H) 7.66 (d, J = 2.5 Hz, 1H), 7.90 (s, 1H), 7.97 (s, 1H); 13C NMR (125
MHz, DMSO):43.5, 128.8, 129.7, 132.0, 133.9, 139.5, 142.1, 155.4; IR (KBr): 695, 799,
1002, 1090, 1193, 1319, 1428, 1577, 1900, 2354, 2930, 3243, 3424; HRMS calcd for
C12H14N3: 220.0642, found: 220.0672.
Synthesis of N,5-dibenzyl-4-phenylthiazol-2-amine (5a): In a 25 mL round bottomed flask,
176 mg (1.0 mmol) of 4-phenylthiazol-2-amine 4a, 324 mg (3.0 mmol) of benzyl alcohol, 40
mg (1.0 mmol) of sodium hydroxide (NaOH) and 1.0 mL of toluene were placed. The
reaction flask was heated at130 °C for 28 h in an oil bath. After completion of the reaction,
the flask was allowed to attain room temperature, and 20 mL of water was added. The
product was extracted with EtOAc (30 mL × 3). Removal of the organic solvent under
reduced pressure, the residue left out was subjected to column chromatography on silica gel
using dichloromethane/ethyl acetate (95:5) as eluent. After removal of the solvent, 5a was
obtained in 81% yield (288 mg; 0.81 mmol). 1H NMR (500 MHz, DMSO): ppm 4.08 (s, 2H),
4.45 (d, J = 5.5 Hz, 2H), 7.19 – 7.26 (m, 4H), 7.28 – 7.34 (m, 5H), 7.37 – 7.40 (t, J = 7.5 Hz,
4H), 7.57 (d, J = 7.5 Hz, 2H), 8.00 (t, J = 5.5 Hz, 1H); 13C NMR (125 MHz, DMSO): 32.6,
47.9, 119.3, 126.8, 127.4, 127.6, 127.9, 128.4, 128.7, 129.0, 135.8, 139.7, 140.9, 146.5,
166.0; IR (KBr):702, 845, 1025, 1165, 1232, 1331, 1423, 1449, 1490, 1569, 2949, 3024,
3183, 3450. HRMS calcd for C23H21N2S: 357.1425, found: 357.1455.
N-benzyl-4-phenylthiazol-2-amine (5a̍ ):
Yield 12% (32 mg); 1H NMR (500 MHz, DMSO): δ 4.51 (d, J = 6 Hz, 2H), 7.04 (s, 1H) 7.25
(t, J = 7.5 Hz, 2H), 7.32 – 7.41 (m, 6H), 7.82 (d, J = 7.5 Hz, 2H), 8.18 (t, J = 5.5 Hz, 1H); 13C
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NMR (125 MHz, DMSO): 48.2, 101.6, 126.0, 127.4, 127.7, 128.0, 128.7, 128.9, 135.2,
139.7, 150.3, 168.8; IR (KBr): 698, 726, 974, 1023, 1065, 1106, 1334, 1424, 1482, 1585,
2892, 2929, 2977, 3025, 3057, 1101, 3212, 3429. HRMS calcd for C16H15N2S: 267.0957,
found: 267.0973.
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N,5-bis(4-methoxybenzyl)-4-phenylthiazol-2-amine (5b):
Yield 78% (324 mg); 1H NMR (500 MHz, DMSO): δ 3.70 (s, 3H), 3.71 (s, 3H), 4.00 (s, 2H),
4.35 (d, J = 6 Hz, 2H), 6.85 – 6.90 (m, 4H), 7.09 (d, J = 8.5 Hz, 2H), 7.28 – 7.31 (m, 3H),
7.38 (t, J = 7.5 Hz, 2H), 7.57 (d, J = 7 Hz, 2H) 7.89 (t, J = 6Hz, 1H); 13C NMR (125 MHz,
DMSO): 31.8, 47.4, 55.4, 114.1, 114.3, 120.0, 127.6, 128.4, 128.7, 129.3, 129.5, 131.6,
132.8, 135.8, 146.1, 158.2, 158.7, 165.9; IR (KBr): 695, 804, 1030, 1164, 1245, 1294, 1427,
1510, 1590, 2898, 2939, 3098, 3204, 3425. HRMS calcd for C25H25N2O2S: 417.1637, found:
417.1653.
N,5-bis(4-chlorobenzyl)-4-phenylthiazol-2-amine (5c):
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Yield 82% (348 mg); H NMR (500 MHz, DMSO): δ 4.07 (s, 2H), 4.42 (d, J = 6 Hz, 2H),
7.20 (d, J = 8.5 Hz, 2H), 7.31 (t, J = 7.5 Hz, 1H), 7.35 – 7.41 (m, 8H), 7.51 (d, J = 7.5 Hz,
13
2H), 8.05 (t, J = 6Hz, 1H); C NMR (125 MHz, DMSO): 31.4, 46.6, 118.3, 127.2, 127.9,
128.1, 128.4, 129.2, 129.8, 130.9, 130.9, 131.4, 135.1, 138.3, 139.3, 146.2, 165.4; IR (KBr):
700, 774, 808, 1012, 1088, 1238, 1326, 1408, 1487, 1571, 1738, 2924, 2956, 3081, 3188,
3436. HRMS calcd for C23H19Cl2 N2S: 425.0646, found: 425.0657.
N,5-dibenzyl-4-(4-tert-butylphenyl)thiazol-2-amine (5d):
Yield 83% (342 mg); 1H NMR (500 MHz, DMSO): δ 1.28 (s, 9H), 4.07 (s, 2H), 4.42 (d, J = 6
Hz, 2H), 7.19 – 7.25 (m, 4H), 7.29 – 7.40 (m, 8H), 7.47 (d, J = 8.5 Hz, 2H), 7.96 (t, J = 6
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Hz, 1H); C NMR (125 MHz, DMSO): 31.5, 32.6, 34.7, 47.8, 118.7, 125.4, 126.8, 127.3,
127.9, 128.1, 128.4, 128.7, 129.0, 133.0, 139.8, 140.9, 146.4, 150.0, 165.9; IR (KBr): 711,
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844, 973, 1023, 1111, 1163, 1329, 1422, 1451, 1494, 1593, 2363, 2898, 2959, 3105, 3220,
3426. HRMS calcd for C27H29N2S: 413.2051, found: 413.2071.
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4-(4-tert-Butylphenyl)-N,5-bis(4-methylbenzyl)thiazol-2-amine (5e):
Yield 80% (352 mg); 1H NMR (500 MHz, DMSO): δ 1.28 (s, 9H), 2.26 (s, 6H), 4.00 (s, 2H),
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4.35 (d, J = 5 Hz, 2H), 7.06 – 7.13 (m, 6H), 7.23 (d, J = 7.5 Hz, 2H), 7.38 (d, J = 8 Hz, 2H),
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7.46 (d, J = 8 Hz, 2H), 7.86 (t, J = 5.5 Hz, 1H); C NMR (125 MHz, DMSO): 20.7, 20.8,
31.2, 32.0, 34.4, 47.4, 118.7, 125.1, 127.6, 127.8, 128.0, 128.9, 129.2, 132.7, 135.5, 136.1,
136.4, 137.6, 146.0, 149.7, 165.5; IR (KBr): 678, 793, 842, 980, 1019, 1109, 1169, 1331,
1424, 1460, 1509, 1594, 1799, 1894, 2365, 2961, 3102, 3208, 3423. HRMS calcd for
C29H33N2S: 441.2364, found: 441.2379.
4-(4-tert-Butylphenyl)-N,5-bis(4-methoxybenzyl)thiazol-2-amine (5f):
Yield 80% (377 mg); 1H NMR (500 MHz, DMSO): δ 1.28 (s, 9H), 3.71 (s, 3H), 3.72 (s, 3H),
3.99 (s, 2H), 4.33 (d, J = 5.5 Hz, 2H), 6.85 – 6.89 (m, 4H), 7.10 (d, J = 7.5 Hz, 2H), 7.28 (d,
J = 7.5 Hz, 2H), 7.39 (d, J = 7 Hz, 2H), 7.49 (d, J = 7.5 Hz, 2H), 7.85 (t, J = 5.5 Hz, 1H); 13C
NMR (125 MHz, DMSO): 31.5, 31.8, 34.7, 47.4, 55.4, 114.1, 114.3, 119.4, 125.4, 128.1,
129.3, 129.4, 131.7, 132.9, 133.1, 146.1, 149.9, 158.2, 158.7, 165.8; IR (KBr): 678, 730,
808, 1031, 1106, 1168, 1248, 1427, 1459, 1510, 1593, 1876, 1919, 2361, 2959, 3212, 3423.
HRMS calcd for C29H33N2O2S: 473.2262, found: 473.2288.
4-(4-tert-Butylphenyl)-N,5-bis(4-chlorobenzyl)thiazol-2-amine (5g):
Yield 81% (389 mg); 1H NMR (500 MHz, DMSO): δ 1.27 (s, 9H), 4.06 (s, 2H), 4.41 (d, J = 6
Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.35 – 7.40 (m, 8H), 7.44 (d, J = 8.5 Hz, 2H), 8.02 (t, J = 6
13
Hz, 1H); C NMR (125 MHz, DMSO): 31.5, 31.9, 34.7, 47.1, 118.2, 125.5, 128.1, 128.6,
128.9, 129.8, 130.3, 131.4, 131.9, 132.8, 138.9, 139.9, 146.7, 150.1, 165.8; IR (KBr):687,
729, 811, 1013, 1090, 1267, 1328, 1360, 1406, 1458, 1489, 1575, 1896, 2362, 2962, 3087,
3197, 3424. HRMS calcd for C27H27Cl2N2S: 481.1272, found: 481.1278.
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4-(4-tert-Butylphenyl)-N,5-bis(2-chlorobenzyl)thiazol-2-amine (5h):
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Yield 85% (408 mg); H NMR (500 MHz, DMSO): δ 1.27 (s, 9H), 4.15 (s, 2H), 4.52 (d, J =
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5.5 Hz, 2H), 7.24-7.35 (m, 5H), 7.39 (d, J = 8.5 Hz, 2H), 7.43 - 7.49 (m, 5H), 8.01 (t, J = 5.5
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Hz, 1H); C NMR (125 MHz, DMSO): 30.5, 31.2, 34.4, 45.1, 116.9, 125.2, 127.3, 127.7,
127.7, 128.7, 128.9, 129.3, 129.5, 129.5, 130.3, 132.5, 132.5, 132.9, 136.4, 137.9, 146.4,
149.9, 165.2; IR (KBr): 691, 750, 841, 1040, 1118, 1168, 1242, 1326, 1442, 1587, 2874,
2961, 3094, 3200, 3425. HRMS calcd for C27H27Cl2N2S: 481.1273, found: 481.1301.
N,5-dibenzyl-4-p-tolylthiazol-2-amine (5i):
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Yield 80% (296 mg); H NMR (500 MHz, DMSO): δ 2.30 (s, 3H), 4.05 (s, 2H), 4.42 (d, J =
5.5 Hz, 2H), 7.17 – 7.25 (m, 6H), 7.28 – 7.37 (m, 6H), 7.44 (d, J = 8 Hz, 2H), 7.96 (t, J = 6
13
Hz, 1H); C NMR (125 MHz, DMSO): 20.9, 32.3, 47.6, 118.4, 126.5, 127.0, 127.6, 128.0,
128.1, 128.4, 128.7, 129, 13.76, 136.6, 139.4, 140.7, 146.2, 165.6; IR (KBr): 693, 723, 827,
975, 1163, 1239, 1329, 1425, 1447, 1495, 1592, 2897, 3205, 3433. HRMS calcd for
C24H23N2S: 371.1583, found: 371.1590.
N,5-bis(2-chlorobenzyl)-4-p-tolylthiazol-2-amine (5j):
1
Yield 81% (355 mg); H NMR (500 MHz, DMSO): δ 2.30 (s, 3H), 4.14 (s, 2H), 4.51 (d, J =
5.5 Hz, 2H), 7.18 (d, J = 8 Hz, 2H), 7.24 – 7.35 (m, 5H), 7.39 (d, J = 8 Hz, 2H), 7.43 (d, J =
7.5 Hz, 2H), 7.47 (d, J = 7.5 Hz, 1H), 7.99 (t, J = 6Hz, 1H); 13C NMR (125 MHz, DMSO):
20.7, 30.3, 45.0, 116.7, 127.0, 127.4, 127.7, 128.4, 128.7, 128.8, 129.1, 129.3, 130.1, 132.3,
132.4, 132.7, 136.2, 136.4, 137.8, 146.3, 165.1; IR (KBr): 695, 744, 825, 1040, 1168, 1234,
1326, 1443, 1505, 1589, 2362, 2890, 2927, 2963, 3064, 3197, 3429. HRMS calcd for
C24H21Cl2N2S: 439.0803, found: 439.0813.
N,5-dibenzyl-4-(4-chlorophenyl)thiazol-2-amine (5k):
1
Yield 80% (312 mg); H NMR (500 MHz, DMSO): δ 4.07 (s, 2H), 4.42 (d, J = 6 Hz, 2H),
7.18 – 7.26 (m, 4H), 7.29 – 7.36 (m, 6H), 7.44 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H),
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8.01 (t, J = 6 Hz, 1H); 13C NMR (125 MHz, DMSO): 32.6, 47.8, 120.1, 126.9, 127.4, 127.9,
128.5, 128.7, 129.0, 130.1, 132.1, 134.6, 139.6, 140.6, 145.0, 166.0; IR (KBr): 696, 754,
835, 973, 1012, 1087, 1164, 1426, 1448, 1483, 1591, 2360, 2898, 3207, 3423. HRMS calcd
for C23H20ClN2S: 391.1036, found: 391.1041.
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N,5-bis(2-chlorobenzyl)-4-(4-chlorophenyl)thiazol-2-amine (5l):
Yield 82% (376 mg); 1H NMR (500 MHz, DMSO): δ 4.16 (s, 2H), 4.53 (d, J = 6Hz, 2H), 7.26
– 7.34 (m, 5H), 7.43 – 7.49 (m, 5H), 7.55 (d, J = 8.5 Hz, 2H), 8.06 (t, J = 5.5 Hz, 1H); 13C
NMR (125 MHz, DMSO): 30.5, 45.2, 118.5, 127.3, 127.7, 128.5, 128.8, 128.9, 129.3, 129.5,
129.7, 130.4, 131.9, 132.5, 132.9, 134.2, 136.3, 137.7, 145.0, 165.45; IR (KBr): 693, 746,
832, 1040, 1089, 1164, 1234, 1328, 1443, 1587, 2891, 3197, 3419. HRMS calcd for
C23H18Cl3N2S: 459.0256. found: 459.0258.
Acknowledgment
We thank Dr. A.V. Boricha, Dr. E. Suresh, Mr. A. K. Das of this institute for recording NMR
Single crystal and mass respectively. We thank Dr. H. N. Gopi for HR-MS help. R.R.D.; V.
P. and D. C. M. are thankful to UGC, New Delhi, India for their fellowships. DST, Govt.
India (SR/S1/OC-13/2011) and CSIR-CSMCRI (CSC-0105) are greatly acknowledged for
financial support.
Supporting Information Available. Copies of NMR spectra for all compounds and HRMS
spectra for new compounds free of charge via the internet at http://pubs.acs.org.
Crystallographic data for compound 5h (CCDC- 916195) can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
References
(1) Smith, M. B.; March, J. In March’s Advanced Organic Chemistry; 6th ed., Wiley-
Interscience: New York, 2007.
(2) Baxter, E. W. and Reitz, A. B. Organic Reactions. John Wiley & Sons: New York, 2004.
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(3) Hartwig, J. F. H. Acc. Chem. Res. 2008, 41, 1534.
5
6
7
8
(4) Surry, D. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
(5) Lawerencem, S. A. Amines: Synthesis Properties and Applications, Cambridge
University, Cambridge, 2004.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) Vollhardt, K. P. C.; Schore, N. E. Organic Chemistry: Structure and Function, 5th ed.,
Freeman, W. H. New York, 1999.
(7) Nunez Magro, A. A.; Eastham, G. R.; Cole-Hamilton, D. J. Chem. Commun. 2007, 3154.
(8) Seayad, A.; Ahmed, M.; Klein, H.; Jackstell, R.; Gross, T.; Beller, M. Science 2002, 297,
1676.
(9) Li, F.; Kang, Q.; Shan, H.; Chen, L.; Xie, J. Eur. J. Org. Chem. 2012, 5085 and
references therein.
(10) Guillena, G.; RamsÓn, D. J. ; Yus, M. Chem. Rev. 2010, 110, 1611.
(11) Nef, J. U. Justus Liebigs Ann. Chem. 1901, 318, 137.
(12) Lazier, W. A.; Adkins, H. J. Am. Chem. Soc. 1924, 46, 741.
(13) Sprinzak, Y. J. Am. Chem. Soc. 1956, 78, 3207.
(14) Miyano, S. Chem. Pharm. Bull. 1965, 13, 1135.
(15) Zvezdina, A.; Pozharskii, A. F.; Sokolov, V. I. Chem. Heterocycl. Compd. 1970, 6, 389.
(16) Miyano, S.; Nakao, M. Chem. Pharm. Bull. 1972, 20, 1328.
(17) Xu, Q.; Li, Q.; Zhu, X.; Chen, J. Adv. Synth. Catal. 2013, 355, 73.
(18) Donthiri, R. R.; Patil, R.D.; Adimurthy, S. Eur. J. Org. Chem. 2012, 4457.
(19) Tang and co-workers have also described the activation of alcohol by base in presence of
amines see: Xu, J.; Zhuang, R.; Bao, L.; Tang, G.; Zhao, Y. Green Chem. 2012, 14, 2384.
(20) Mohan, D. C.; Rao, S. N.; Adimurthy, S. J. Org. Chem. 2013, 78, 1266.
(21) Patil, R. D.; Adimurthy, S. Adv. Synth. Catal. 2011, 353, 1695.
(22) Chunavala, K. C.; Joshi, G.; Suresh, E.; Adimurthy, S. Synthesis 2011, 635.
(23) Chunavala, K. C.; Adimurthy, S. Synth. Commun. 2011, 41, 1843.
(24) Nageswara Rao, S.; Chandra Mohan, D.; Adimurthy, S. Org. Lett. 2013, 15, 1496.
(25) Cavalleri, B.; Turconi, M.; Tamborini, G.; Occelli, E.; Cietto, G.; Pallanza, R.; Scotti,
R.; Berti, M.; Roman, G.; Parenti, F. J. Med. Chem. 1990, 33, 1470.
(26) Das, J.; Moquin, R. V.; Lin, J.; Liu, C.; Doweyko, A. M.; Defex, H. F.; Fang, Q.; Pang,
S.; Pitt, S.; Shen, D. R.; Schieven, G. L.; Barrish, J. C.; Wityak, J. Bioorg. Med. Chem. Lett.
2003, 13, 2587.
(27) Byeon, S. R.; Jin, Y. J.; Lim, S. J.; Lee, J. H.; Yoo, K. H.; Jung, S. K.; Ohb, S. J.;
Kim, D. J.; Bioorg. Med. Chem. Lett. 2007, 17, 4022.
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5
6
(28) Sun, Z. Y.; Zhu, Z.; Ye, Y.; McKittrick, B.; Czarniecki, M.; Greenlee, W.; Mullins, D.;
Guzzi, M. Bioorg. Med. Chem. Lett. 2009, 19, 6801.
7
8
9
(29) Basavarajaiah, S. M.; Mruthyujayaswamy, B. H. M. Indian J. Chem. 2010, 49B, 1117.
(30) El-Subbagh, H. I.; Abadi, A. H.; Lehmann, J. Arch. Pharm. Pharm. Med. Chem. 1999,
332, 137.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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35
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(31) Dykhuizen, E. C.; May, J. F.; Tongpenyai, A.; Kiessling, L. L. J. Am. Chem. Soc. 2008,
130, 6706.
(32) Zhang, T.; Yan, Z.; Sromek, A.; Knapp, B. I.; Scrimale, T.; Bidlack, J. M.; Neumeyer,
J. L. J. Med. Chem. 2011, 54, 1903.
(33) Li, F.; Shan, H.; Kang, Q.; Chen, L. Chem. Commun. 2011, 47, 5058.
(34) Li, F.; Shan, H.; Chen, L.; Kang, Q.; Zou, P. Chem. Commun. 2012, 48, 603.
(35) Zhang, W.; Yue, Y.; Yu, D.; Song, L.; Xu, Y. Y.; Tian, Y. J .; Guo, Y. J.; Adv. Synth.
Cat. 2012, 354, 2283.
(36) Martinez-Asencio, A.; Yus, M.; Ramon, D. J. Synthesis 2011, 3730.
(37) Ma, D.; Lu, X.; Shi, L.; Zhang, H.; Jiang. Y.; Liu, X. Angew. Chem., Int. Ed. 2011, 50,
1118.
(38) Saha, P.; Ramana, T.; Purkait, N.; Ali, M. A.; Paul, R.; Punniyamurthy, T. J. Org. Chem.
2009, 74, 8719.
(39) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem., Int. Ed. 2009, 48, 9127.
(40) Wang, X.; Zhang, B.; Wang, D. Z.; Tetrahedron 2011, 67, 3406.
(41) Lewis, G. E. J. Org. Chem. 1965, 30, 2433.
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